Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is defined by the presence
of extracellular amyloid-beta plaques and intracellular tau-protein-containing neurofibrillary tangles in
the brain1. There are currently no effective treatments available and removing amyloid-beta has thus far
been ineffective in clinical trials. As such, my project will focus on tau pathology and its mechanisms
at the neural circuit level, with a view to elucidating the role of tau in pathoprogression of AD and
informing future circuit-level therapeutic approaches.
Tau pathology in humans involves propagation of tau beginning in the entorhinal cortex, spreading to
the hippocampus, then the cerebral cortex2, and this propagation parallels the clinical stages of the
disease. However, the mechanism(s) linking protein accumulation and cognitive decline is unknown.
Neuronal hyperexcitability precedes tau propagation and accumulation in disease models, and there
is evidence that neuronal activity enhances tau propagation and pathology in vivo3, although the
mechanism for this is not established. Furthermore, there is evidence for tau-dependent suppression
of activity and silencing of neurons4, with cell-type specific selective vulnerability5,6.
The aim of this project will be to study neuronal dysfunction in the context of tau at the circuit level,
employing complimentary large-scale electrophysiological (Neuropixels), two- and one-photon
calcium and voltage imaging, and behavioural studies to answer two key questions:
How does activity in neural circuits affect tau propagation?
How does tau propagation affect activity in neural circuits, and thereby cognition?
In addressing these questions, I will investigate mechanisms for the interaction between tau and
neural activity in multiple Alzheimer's disease mouse models, which will advance our understanding
of the disease pathogenesis, and have relevance for therapeutic approaches based on modulating
excitability, potentially in a cell-type specific manner.
Bibliography:
1. Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Primer 7, 1-21 (2021).
2. Busche, M. A. & Hyman, B. T. Synergy between amyloid-beta and tau in Alzheimer's disease. Nat.
Neurosci. 23, 1183-1193 (2020).
3. Wu, J. W. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat.
Neurosci. 19, 1085-1092 (2016).
4. Busche, M. A. et al. Tau impairs neural circuits, dominating amyloid-beta effects, in Alzheimer
models in vivo. Nat. Neurosci. 22, 57-64 (2019).
5. Turkes, E. & Duff, K. E. Cell-type specific selective vulnerability to pathological tau in Alzheimer's
disease. Alzheimers Dement. 16, e043149 (2020).
6. Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability of
excitatory neurons to tau pathology. Nat. Neurosci. 22, 47-56 (2019).